The long term goals of this project are to determine how chemicals from the environment impact human health. These chemicals, commonly called xenobiotics, come in many forms including environmental contaminants, drugs, dietary supplements, and compounds normally found in food and drink. When present in the body, xenobiotics are sensed by proteins known as nuclear receptors. Binding of xenobiotics to nuclear receptors causes these regulators to induce the production of the cellular machinery that detoxifies and exports these compounds from the body. Many of the recent discoveries about xenobiotic sensing nuclear receptors indicates that their affect on gene expression is often in cooperation with regulators of basic cellular metabolism including carbohydrate and lipid homeostasis. This study aims to discover how combinations of transcriptional regulators control the production of detoxification enzymes and exporters in response to ingested xenobiotics. This combinatorial control of detoxification, along with overlapping control of basic cellular metabolism, suggests that xenobiotic presence might impact the basic cellular chemistry of normal metabolism. Therefore, a second aim of this study is to discovery how xenobiotics impact the production of enzymes not involved in detoxification through their induction of the xenobiotic sensing nuclear receptors. Research with the nematode, Caenorhabditis elegans, offers a powerful system in which to accomplish these aims. Through a high-throughput screen using a technique known as RNA mediated interference, the complete set of transcriptional regulators in C. elegans will be analyzed for their requirement in xenobiotic defense. One such transcriptional regulator is known: NHR-8, which is very similar in structure and function to the xenobiotic sensing nuclear receptors in humans. Transcriptional regulators discovered in the screen will therefore also be analyzed for their cooperation with NHR-8 in gene regulation. NHR-8 is hypothesized to control the production of enzymes involved in normal cellular metabolism, such as lipid and carbohydrate metabolism, as well as those of xenobiotic detoxification. Thus, NHR-8 offers a unique entryway into study of the intersections between normal and xenobiotic metabolism. Targets of NHR-8's transcriptional regulation will be analyzed for their expression during xenobiotic challenge. Additionally, the role of NHR-8 in xenobiotic sensing will be further characterized. Through these two aims, this research will contribute to the understanding of how pollutants, drugs, and other chemicals impact the body's metabolic state and the removal of offending and helpful xenobiotics. PUBLIC HEALTH RELEVANCE: This project is designed to discover how chemicals in food, drugs, and the environment impact human metabolism. Recent discoveries indicate a link between these chemicals and basic cellular functions such as energy metabolism and hormonal signaling. The research proposed in this project will help uncover the mechanisms that allow such foreign chemicals to have unexpected and deleterious consequences on human health.